title: The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance.
abstract: Glioblastoma remains one of the most lethal types of cancer, and is the most common brain tumour in adults. In particular, tumour recurrence after surgical resection and radiation invariably occurs regardless of aggressive chemotherapy. Here, we provide evidence that the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) exerts simultaneous influence over invasion, chemoresistance and tumourigenesis in glioblastoma. ZEB1 is preferentially expressed in invasive glioblastoma cells, where the ZEB1-miR-200 feedback loop interconnects these processes through the downstream effectors ROBO1, c-MYB and MGMT. Moreover, ZEB1 expression in glioblastoma patients is predictive of shorter survival and poor Temozolomide response. Our findings indicate that this regulator of epithelial-mesenchymal transition orchestrates key features of cancer stem cells in malignant glioma and identify ROBO1, OLIG2, CD133 and MGMT as novel targets of the ZEB1 pathway. Thus, ZEB1 is an important candidate molecule for glioblastoma recurrence, a marker of invasive tumour cells and a potential therapeutic target, along with its downstream effectors.
authors.affiliation: Department of Neurosurgery, University of Florida, Gainesville, FL, USA. fas@ufl.edu
authors.forename: Florian A
authors.initials: FA
authors.lastname: Siebzehnrubl
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Silver
authors.forename: Bugra
authors.initials: B
authors.lastname: Tugertimur
authors.forename: Loic P
authors.initials: LP
authors.lastname: Deleyrolle
authors.forename: Dorit
authors.initials: D
authors.lastname: Siebzehnrubl
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sarkisian
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Devers
authors.forename: Antony T
authors.initials: AT
authors.lastname: Yachnis
authors.forename: Marius D
authors.initials: MD
authors.lastname: Kupper
authors.forename: Daniel
authors.initials: D
authors.lastname: Neal
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Nabilsi
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kladde
authors.forename: Oleg
authors.initials: O
authors.lastname: Suslov
authors.forename: Simone
authors.initials: S
authors.lastname: Brabletz
authors.forename: Thomas
authors.initials: T
authors.lastname: Brabletz
authors.forename: Brent A
authors.initials: BA
authors.lastname: Reynolds
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Steindler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D000077204:Temozolomide; D014157:Transcription Factors / Q000378:metabolism*; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000097905:Roundabout Proteins
chemical_list: D000970:Antineoplastic Agents; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D003606:Dacarbazine; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D020598:Proto-Oncogene Proteins c-myb; D011971:Receptors, Immunologic; D000077204:Temozolomide; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000097905:Roundabout Proteins; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; C515491:MGMT protein, human
keywords: EMT; brain; cancer stem cell; glioma; xenograft